INDIANAPOLIS -- Researchers at the Indiana University School of Medicine have identified a series of molecular signals that control a crucial process of heart development spanning a period from shortly before birth into the post-natal period.

The research reveals for the first time how the wiring for the body's sympathetic nervous system -- the so-called "fight or flight" system" -- gets installed into the still-developing newborn heart and the important role it plays in heart function. The research was published March 24 by the Proceedings of the National Academy of Sciences.

The research, by professor of pediatrics Simon J. Conway, Ph.D., and his colleagues sheds new light on a poorly understood period of heart development shortly before and after birth, when sympathetic nerves colonize and are assimilated into the developing fetal heart.

Disruption of this system can have deadly consequences, Dr. Conway said, including significant slowing of the heartbeat, known as bradycardia, and electrophysical problems. These birth defects mimic a rare disease called LEOPARD syndrome, in which patients have a disruptive mutation in the signaling protein SHP-2.

Using a series of mouse models of cardiac development bred to enable specific genes to be "knocked out" in specific tissues and at defined ages, the researchers determined that SHP-2 plays a key role in the development process. Lack of SHP-2 caused a cascade of molecular signals that resulted in the significant reduction of another downstream protein called pERK.

Using an additional mouse model, the researchers were able to reverse the nerve maldevelopment and bradycardia issues by restoring production of the pERK protein even in mice with the SHP-2 mutation.

"These mouse models bring us closer to understanding the causes of these birth defects and treating human patients with such mutations," said Dr. Conway, noting that certain compounds can promote pERK protein production, although much work would need to be done to enable them to target the proper heart tissues.

Additional authors include first author Jacquelyn D. Lajiness, Paige Snider and Jian Wang of the IU School of Medicine; Gen-Sheng Feng of the University of California San Diego; and Maike Krenz of the University of Missouri.

The research was supported in part by American Heart Association predoctoral grant 13PRE16920038, the Riley Children's Foundation, Indiana University Department of Pediatrics (Neonatal-Perinatal Medicine) and National Institutes of Health grant R01HL60714.